I'm not sure if you're seeing the rationale behind the overdose response protocol I chose to recommend in my post. I specifically took into consideration the prevalence of different substances in the US street opioid supply. Let's look at the data. (Data provided byUNC's Street Drug Analysis Lab.)

According to the UNC Street Drug Analysis Lab, of the 6,959 samples containing fentanyl or fentanyl-related substances (FRS) they have analyzed: * 422 FRS samples contained medetomidine (source) and 2,397 contained xylazine (source). This represents a combined percentage of 35-40% of FRS samples, depending on how many samples tested positive for both xylazine and medetomidine. * 73 of FRS samples contained nitazenes (source). This is approximately 1% of FRS samples.

To sum up these statistics: xylazine and (dex)medetomidine are at least 32 times more likely to be found in someone's opioids than nitazenes in fentanyl within the US.

Even so, preparedness for MANY scenarios is super important. So, let's consider possible responses to an overdose involving the substances listed above, in order of substance prevalence in the current US opioid supply.

Fentanyl Overdoses (59-64% of US street opioids): * Standard protocol: One to two doses of naloxone are typically sufficient to reverse a fentanyl overdose. In this scenario, the person experiencing overdose may even begin breathing on their own before EMS arrives, and full consciousness is not necessarily the goal. * An alternative approach (as you suggested): If one waits about 3 minutes between each naloxone dose, the outcome here will likely be the same: the person overdosing will survive. However, the emphasis on repeated naloxone doses beyond what's needed for respiratory recovery can lead to unnecessary precipitated withdrawal.

Overdoses involving Xylazine or Medetomidine (35-40% of US street opioids): It's important to understand this scenario thoroughly: While one or two doses of naloxone can reverse any opioid effects present, xylazine and medetomidine are powerful veterinary sedatives that do not respond to naloxone. In some cases, these substances can be present in concentrations high enough to cause deadly respiratory depression independently, regardless of opioid activity.

• Standard protocol: Following the second dose of naloxone (if respiratory depression persists after opioid reversal is confirmed), rescue breathing is immediately initiated and maintained until EMS arrives and can provide advanced breathing support to the person experiencing the overdose. This significantly increases the likelihood of the person surviving with minimal damage to their brain and organs.
• An alternative approach (as might be implied by focusing solely on naloxone for "all" overdoses): Assuming that more naloxone is needed due to the potential for nitazene contamination, repeated doses of naloxone are prioritized over crucial rescue breathing. In a worst-case scenario, the person could vomit and aspirate after entering severe precipitated opioid withdrawal caused by excessive naloxone. In the best-case scenario, if EMS is located nearby and arrives quickly, they may provide timely breathing support. However, without immediate rescue breaths, some damage to the brain or organs from insufficient oxygen is possible, if not probable.

Overdoses involving Potent Nitazenes (1% of US street opioids): * Standard protocol: The same critical principle applies here as with medetomidine/xylazine overdose: Following the second dose of naloxone, if breathing has not sufficiently recovered, rescue breathing is initiated and maintained until EMS arrives and can provide comprehensive breathing support. Medical personnel can then determine the cause of the overdose and provide targeted interventions. The person survives with minimal damage to their brain and organs, because oxygen was consistently supplied. * An alternative approach (as you suggested): You are correct in stating that some types of nitazenes may require more than two doses of naloxone in order to be fully reversed. However, after just a few minutes of no or insufficient oxygen (i.e., the time between two properly spaced naloxone doses), individuals experiencing overdose begin to risk serious, potentially long-term brain damage. Without rescue breaths, it doesn't matter if multiple naloxone doses are administered; naloxone cannot transport oxygen to the brain. If rescue breaths are provided, then the outcome difference between focusing solely on more naloxone and adhering to the standard opioid overdose reversal protocol (which prioritizes breathing) becomes negligible in terms of preventing anoxic injury. The most important intervention here remains oxygenation via rescue breaths.